Chronic thromboembolic pulmonary hypertension and the post-pulmonary embolism (PE) syndrome.

Over a third of patients surviving acute pulmonary embolism (PE) will experience long-term cardiopulmonary limitations. Persistent thrombi, impaired gas exchange, and altered hemodynamics account for aspects of the postpulmonary embolism syndrome that spans mild functional limitations to debilitating chronic thromboembolic pulmonary hypertension (CTEPH), the most worrisome long-term consequence. Though pulmonary endarterectomy is potentially curative for the latter, less is understood surrounding chronic thromboembolic disease (CTED) and post-PE dyspnea. Advances in pulmonary vasodilator therapies and growing expertise in balloon pulmonary angioplasty provide options for a large group of patients ineligible for surgery, or those with persistent postoperative pulmonary hypertension. In this clinical review, we discuss epidemiology and pathophysiology as well as advances in diagnostics and therapeutics surrounding the spectrum of disease that may follow months after acute PE.

Fetal Supraventricular Tachycardia: What the Adult Cardiologist Needs to Know.

Fetal supraventricular tachycardia management is challenging, with consequences for both the fetus and the mother. If left untreated, fetal hydrops may ensue, at which point delivery and treatment of the arrhythmia is preferred. However, if the fetus is not at term nor near-term, significant doses of antiarrhythmics may be needed to achieve adequate transplacental bioavailability. Although digoxin has classically been the mainstay of treatment, the use of flecainide or sotalol as monotherapy or in combination with digoxin is being studied. Interdisciplinary team management and shared decision-making between the physician and patient are key to achieving successful outcomes. Adult cardiologists, particularly inpatient consultation services or through burgeoning cardio-obstetrics programs, may, in some practice settings, be asked to evaluate or comanage pregnant women with fetal arrhythmia.

Thromboembolic complications of COVID-19.

The symptomology of patients afflicted with novel 2019 coronavirus disease (SARS-CoV-2 or COVID-19) has varied greatly, ranging from the asymptomatic state to debilitating hypoxemic respiratory failure caused by severe atypical viral pneumonia. Patients may also develop a hyper-inflammatory state that can lead to multi-organ failure. It has become increasingly apparent that, as part of the hyper-inflammatory state, COVID-19 infection increases susceptibility to systemic thromboembolic complications that can contribute to rapid clinical deterioration or demise. This article aims to review imaging features of various systemic thrombotic complications in six patients with moderate to severe disease. This case series includes examples of pulmonary embolism, stroke, right ventricular thrombosis, renal vein thrombosis, and aortic thrombosis with leg ischemia.

Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute pulmonary embolism: A multicenter comparison of patient-centered outcomes.

Both catheter-directed thrombolysis (CDT) and ultrasound-assisted thrombolysis (USAT) are novel treatment modalities for patients presenting with acute pulmonary embolism (PE). The objective of this study was to compare clinical and quality-of-life (QOL) outcomes for patients undergoing either treatment modality. We retrospectively studied 70 consecutive patients treated with either CDT or USAT over 3 years at a multicenter health system. The primary clinical efficacy endpoint was right ventricular systolic pressure (RVSP) reduction post-procedurally. Safety endpoints were mortality and bleeding incidents based on Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) criteria. Long-term QOL was assessed using the 36-Item Short-Form Health Survey (SF-36) via phone interview. Thirty-seven patients (53%) in our study underwent USAT and 33 (47%) patients were treated with conventional CDT. Among all patients studied, 96% had echocardiographic evidence for right ventricular strain on admission. Mean RVSP decreased by 18 ± 13 mmHg in the USAT group post-procedurally as compared to 14 ± 16 mmHg in the CDT group, without significant difference between groups ( p = 0.31). Rates of moderate and severe bleeding were largely identical between USAT and CDT groups (USAT: 3%; CDT: 0%; p = 0.09). There was no death in either group during admission. At long-term follow-up, there was no significant difference in QOL between both treatment modalities in all eight functional domains of SF-36. Our retrospective study demonstrated using USAT over conventional CDT for acute submassive or massive PE did not yield additional clinical, safety, or long-term QOL benefit.

Re-evaluating the Appropriateness of Non-invasive Arterial Vascular Imaging and Diagnostic Modalities.

OPINION STATEMENT: Imaging modalities to detect and diagnose vascular disease have become increasingly popular in recent years, owing in large part to their availability and accessibility. The American College of Cardiology Foundation published a two-part Appropriate Use Criteria (AUC) guidance document for both peripheral vascular imaging and physiologic testing several years ago. In the years since their publication, a number of important studies have challenged previously held beliefs about appropriateness of vascular diagnostic testing. To address the ever-changing landscape, we offer a review of the current appropriate use guidelines for arterial vascular diagnostic procedures and relevant major studies published in the interim. We aim to provide a comprehensive review of appropriate arterial vascular diagnostic imaging testing for the cardiovascular clinician.

Building a Successful Superficial Venous Program.

OPINION STATEMENT: As the treatment of superficial venous insufficiency transitioned from the hospital to the office setting, a remarkable increase in provider interest developed. However, the novelty of the disease process and procedural opportunities are tempered by the challenges associated with knowledge acquisition, skill development, strategic planning, and program development. Only a unique recipe of clinical growth, technical acumen, management skill, operational efficiency, and financial sense lead to program success. Despite the variety of skills required, treating superficial venous insufficiency is obtainable for both the formally and non-formally trained physicians with sufficient commitment, education, and resources.

Building a Critical Limb Ischemia Program.

OPINION STATEMENT: The need to develop highly qualified, multidisciplinary critical limb ischemia (CLI) programs has gained significant momentum. Due to the systemic nature of the disease, patients with CLI are inherently medically complex and often present with multiple comorbidities. Successful care for these patients depends on community screening, early referral, accurate diagnosis, risk stratification, risk factor modification, invasive and non-invasive treatment strategies, and appropriate surveillance. Patients with CLI are often treated by multiple subspecialists-often lacking a unified team which could lead to inefficiencies and redundancy. Establishing an effective critical limb ischemia program relies on the joint efforts of multiple physician specialists, nurses, technicians, wound care specialists, researchers, and administrators who together form an integrated network that is easily accessible to the patient. This article will focus on the various modalities needed to build an advanced critical limb ischemia program, while addressing the challenges facing the medical community in caring for this population.

The fluoro-less and contrast-less peripheral endovascular intervention: a concept for the future today.

INTRODUCTION: Percutaneous endovascular revascularization requires fluoroscopic guidance and radiopaque contrast use. This approach becomes problematic, especially in patients with advanced renal disease or allergies to iodinated contrast medium. The direct (exposure) and indirect (lead garment) burden of radiation affects patients and operators alike. PURPOSE: We propose a completely contrast-free, fluoroscopy-free approach to endovascular diagnostic arterial imaging and percutaneous intervention using available technologies, and outline a timeframe for its implementation. PROJECT DESCRIPTION/METHODOLOGY: Ultrasound imaging of the leg creates a roadmap of the vessel and identifies the lesion of interest. Device-based sensors using a low-powered electromagnetic field allow for wiring of the vessel. This is followed by the use of intravascular ultrasonography and near infrared spectroscopy to characterize the lesion dimensions and composition. After completion of the diagnostic phase of the process, the interventional portion with deployment of an angioplasty balloon and/or stent is performed using the electromagnetic field-guided sensors. FEASIBILITY: The project uses already available technologies. BENEFITS/ANTICIPATED OUTCOMES: This project demonstrates the real potential of performing endovascular peripheral intervention without fluoroscopy or contrast in a practical, user-friendly way with the currently available technology. The prospects in renal function preservation and radiation avoidance for both patients and operators are extremely attractive.

The S curve: a novel morphological finding in the internal carotid artery in patients with fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease commonly affecting the renal and internal carotid arteries (ICAs). A previously unrecognized finding is a redundancy of the mid-distal ICA in FMD patients causing an 'S'-shaped curve. Carotid artery duplex ultrasounds were reviewed in 116 FMD patients to determine S-curve prevalence. FMD patients with an S curve were matched to four control patients divided equally into two groups: (1) age and sex-matched and (2) age ≥70 and sex-matched. S curves were present in 37 (32%) FMD patients. Of these, nine (24%) had angiographic evidence of FMD in their ICA only, 13 (35%) had renal artery FMD only, and 15 (41%) had both ICA and renal FMD. Two patients in the age and sex-matched group had S curves (odds ratio 16.86, 95% CI 3.92-72.48; p<0.0001) while 12 (16.2%) patients in the age ≥70 and sex-matched group had S curves (odds ratio 2.42, 95% CI 1.16-5.03; p=0.016). In conclusion, the S curve is a novel morphological pattern of the mid-distal ICA. While the S curve may not be specific, its presence in individuals <70 years old should alert the clinician to the possibility that FMD is present.

Oral anticoagulants in the management of venous thromboembolism.

Despite advances in diagnosis, prevention, and management, venous thromboembolism (VTE) remains a common cause of morbidity and mortality. For decades, antithrombotic therapy for prevention and treatment of VTE was limited to parenteral agents related to heparin and oral vitamin K antagonists (VKAs). Both classes of anticoagulants are effective, but have limitations, including considerable variability in dose-response, narrow therapeutic margins between the risks of thrombosis and bleeding, and the need to monitor anticoagulation intensity. Over the past decade, the introduction of new oral anticoagulants that specifically inhibit coagulation factors IIa (thrombin) or Xa has changed practice in a variety of clinical situations, including VTE prophylaxis and treatment. In this Review, we outline the use of the novel oral anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban in the prevention and treatment of VTE, and discuss practical considerations for choosing the appropriate drug for each patient. Although the introduction of novel anticoagulant drugs is promising, selecting the optimum strategy for an individual patient requires an understanding of the specific circumstances associated with thrombus formation and the pharmacological properties of each agent.

Peripheral artery disease. Part 1: clinical evaluation and noninvasive diagnosis.

Peripheral artery disease (PAD) is a marker of systemic atherosclerosis. Most patients with PAD also have concomitant coronary artery disease (CAD), and a large burden of morbidity and mortality in patients with PAD is related to myocardial infarction, ischemic stroke, and cardiovascular death. PAD patients without clinical evidence of CAD have the same relative risk of death from cardiac or cerebrovascular causes as those diagnosed with prior CAD, consistent with the systemic nature of the disease. The same risk factors that contribute to CAD and cerebrovascular disease also lead to the development of PAD. Because of the high prevalence of asymptomatic disease and because only a small percentage of PAD patients present with classic claudication, PAD is frequently underdiagnosed and thus undertreated. Health care providers may have difficulty differentiating PAD from other diseases affecting the limb, such as arthritis, spinal stenosis or venous disease. In Part 1 of this Review, we explain the epidemiology of and risk factors for PAD, and discuss the clinical presentation and diagnostic evaluation of patients with this condition.

Peripheral artery disease. Part 2: medical and endovascular treatment.

The treatment of peripheral artery disease (PAD) focuses on risk factor modification, cardiovascular event reduction, limb viability, and symptom improvement. Hypertension, hyperlipidemia, and diabetes mellitus should all be controlled to recommended target levels, and smoking cessation is vital. Antiplatelet therapies, such as aspirin or clopidogrel, should be administered in all patients unless contraindicated. Whenever possible, patients who present with claudication should be offered a regimen comprised of both medical and exercise therapy, which often results in substantial improvement in symptoms. For patients presenting with more-advanced disease, such as acute limb ischemia, critical limb ischemia, and severely-limiting symptoms of PAD, revascularization is often necessary. As a result of the rapid evolution in endovascular revascularization technology and expertise, many patients with PAD can be treated percutaneously. Therefore, in this Review, we will focus on medical therapy and endovascular revascularization of patients with PAD, with reference to surgical bypass in specific clinical scenarios.

Evaluation of right ventricular function and post-operative findings using cardiac computed tomography in patients with left ventricular assist devices.

BACKGROUND: Right ventricular (RV) failure is a major contributor to morbidity and mortality after left ventricular assist device (LVAD) implantation. Accurate evaluation of RV function in patients with LVAD remains challenging. We hypothesized that, after LVAD implantation, electrocardiographic-gated cardiac computed tomography (CCT) allows RV evaluation with higher feasibility and reproducibility compared with echocardiography. METHODS: Thirty-six patients with an implanted LVAD who had 2-dimensional echocardiography and CCT evaluation were studied. RV end-diastolic and end-systolic volumes and ejection fraction were quantified using CCT. RV fractional area change, tricuspid annular plane systolic excursion and RV end-diastolic short-to-long axis ratio were calculated by echocardiography. Intraclass correlation coefficients (ICCs) and Bland-Altman analysis were used to assess intra- and interobserver reproducibility for all measurements. RESULTS: The quality of CCT studies was good in all cases except for one. Intra- and interobserver reproducibility for all CCT measurements was high (interobserver ICC for RV ejection fraction = 0.89, 95% confidence interval 0.74 to 0.95). Echocardiographic indices of RV function and geometry had lower reproducibility. The echocardiographic index that best correlated with the CCT-determined RV ejection fraction was RV fractional area change (r = 0.80, p < 0.001). In addition, CCT detected relevant post-operative findings in 50% of the patients. CONCLUSIONS: CCT is highly effective and reproducible compared with echocardiography for the evaluation of RV function in patients with LVAD support and provides relevant information on post-operative findings. Our results suggest that CCT should be considered as a useful imaging modality in this clinical setting.

Imaging approaches for the study of cell-based cardiac therapies.

Despite promising preclinical data, the treatment of cardiovascular diseases using embryonic, bone-marrow-derived, and skeletal myoblast stem cells has not yet come to fruition within mainstream clinical practice. Major obstacles in cardiac stem cell investigations include the ability to monitor cell engraftment and survival following implantation within the myocardium. Several cellular imaging modalities, including reporter gene and MRI-based tracking approaches, have emerged that provide the means to identify, localize, and monitor stem cells longitudinally in vivo following implantation. This Review will examine the various cardiac cellular tracking modalities, including the combinatorial use of several probes in multimodality imaging, with a focus on data from the past 5 years.

Advanced lipoprotein testing: recommendations based on current evidence.

Low-density lipoprotein cholesterol (LDL-C) level currently is used as the major determinant of lipid- and lipoprotein-associated risk for ischemic cardiovascular disease, and varying levels have become the standard goals of lipid-altering treatment. The predictive value of the LDL-C cholesterol level, however, often is less than that provided by other variables such as non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apoB), and the number of LDL particles measured by nuclear magnetic resonance spectroscopy. This article reviews studies that compare these different lipoprotein variables, describes advanced methodologies of lipoprotein testing, and suggests goals of treatment and clinical situations in which these tests might be ordered.

A hybrid IRF9-STAT2 protein recapitulates interferon-stimulated gene expression and antiviral response.

Type I interferon (IFN) signaling induces the heterotrimeric transcription complex, IFN-stimulated gene factor (ISGF) 3, which contains STAT1, STAT2, and the DNA binding subunit, interferon regulatory factor (IRF) 9. Because IRF9 is targeted to the nucleus in the absence of IFN stimulation, the potential of IRF9 protein for gene regulation was examined using a GAL4 DNA binding domain fusion system. GAL4-IRF9 was transcriptionally active in reporter gene assays but not in the absence of cellular STAT1 and STAT2. However, the inert IRF9 protein was readily converted to a constitutively active ISGF3-like activator by fusion with the C-terminal transcriptional activation domain of STAT2 or the acidic activation domain of herpesvirus VP16. The IRF9 hybrids are targeted to endogenous ISGF3 target loci and can activate their transcription. Moreover, expression of the IRF9-STAT2 fusion can recapitulate the type I IFN biological response, producing a cellular antiviral state that protects cells from virus-induced cytopathic effects and inhibits virus replication. The antiviral state generated by regulated IRF9-STAT2 hybrid protein expression is independent of autocrine IFN signaling and inhibits both RNA and DNA viruses.

Role of metazoan mediator proteins in interferon-responsive transcription.

The interferon (IFN)-induced signal transduction and transcription activation complex, ISGF3, is assembled from three proteins, STAT1, STAT2, and IRF9. Of these components, STAT2 provides a fundamental and essential transcriptional activation function for ISGF3. In the present study, we show that ISGF3-mediated transcription is dependent on STAT2 interactions with DRIP150, a subunit of the multimeric Mediator coactivator complex. Other Mediator subunits, DRIP77 and DRIP130, were found either to bind STAT2 without augmenting ISGF3 transcriptional activity or to enhance ISGF3 transcription without binding STAT2, but only DRIP150 both enhanced IFN-dependent transcription and coimmunoprecipitated with STAT2. Endogenous DRIP150 and STAT2 were able to interact in solution, and DNA affinity chromatography and chromatin immunoprecipitation assays demonstrated that DRIP150 binds to the mature, activated ISGF3-DNA complex and is recruited to target gene promoters in an IFN-dependent fashion. IFN-dependent recruitment of DRIP130 to an ISGF3 target promoter and SRB10-STAT2 coprecipitation suggest indirect association with a multisubunit Mediator complex. The site of STAT2 interaction was mapped to DRIP150 residues 188 to 566, which are necessary and sufficient for interaction with STAT2. Expression of this DRIP150 fragment, but not DRIP150 fragments outside the STAT2 interaction region, suppressed ISGF3-mediated transcriptional activity in a dominant-negative fashion, suggesting a direct functional role of this domain in mediating STAT2-DRIP150 interactions. These findings indicate that the IFN-activated ISGF3 transcription factor regulates transcription through contact with DRIP150 and implicate the Mediator coactivator complex in IFN-activated gene regulation.